Nonthrombogenic articles and method of preparation

ABSTRACT

The disclosure is of articles having reduced thrombogenicity and which are useful for purposes requiring their contact with whole blood. The articles comprise solid, polymeric resin substrates to which there is fixed a compound of the formula: ##STR1## wherein R is alkyl of 12 to 18 carbon atoms, inclusive, R 1  is lower alkyl and A is the negative ion of a soluble salt of heparin. The articles advantageously exhibit low toxicity and excellent blood compatibility when used for purposes which bring them into contact with whole blood for prolonged periods of time.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a Division of U.S. application Ser. No. 76,201, now U.S. Pat.No. 4,302,368, filed Sept. 17, 1979, which is a continuation-in-part ofU.S. patent application Ser. No. 899,342 now abandoned, filed Apr. 24,1978, and it was a continuation of U.S. patent application Ser. No.752,247 filed Dec. 20, 1976, now abandoned, and also acontinuation-in-part of U.S. patent application Ser. No. 888,951, nowabandoned, filed Mar. 22, 1978 and which was a continuation of U.S.patent application Ser. No. 764,474 filed Jan. 31, 1977, now U.S. Pat.No. 4,116,898.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to non-thrombogenic articles and to methods ofreducing thrombogenicity associated with polymer resin articles.

2. Brief Description of the Prior Art

Representative of the prior art are the disclosures of U.S. Pat. Nos.3,457,098; 3,634,123; 3,810,781; 3,846,353; and 4,118,485. As succinctlystated in U.S. Pat. No. 3,846,353, "It has been known for many yearsthat a basic problem in the development of prostheses for intravascularreplacement lies with the complicated processes occurring at theblood-graft interface. The addition of a solid foreign material to theblood stream results in clot formation on that material. This interfaceactivity occurs no matter what the foreign material might be. Porousprosthetics have proven to be useful in the larger vessel, but havefailed when adapted to the smaller artery. Certain non-porous materialshave been used but also have demonstrated various disadvantages. Solidor imperforate materials are preferred in the field of artificialinternal organ development. Pumping chambers, arteries and materials forencompassing structures having moving parts would demand the property ofelasticity as its constituent, prompting an additional requirement ofthe ideal vascular prosthetic material. It would also be advantageous ifthat same material could be varied in its elastic properties to thepoint of rigidity.

"Naturally, polymers, both natural and synthetic and particularlycertain synthetic plastics have come to the fore as preferred materialsfor these prosthetics. Their major drawback, however, is theirthrombogenicity. Even though plastics are used in various apparatus suchas heart-lung machines, kidney machines, and artificial heart valves andpatches, the tendency of these materials to cause coagulationnecessitates the use of anticoagulants such as heparin. Even suchplastics as Teflon (polytetrafluoroethylene) and the silicone rubberswhich are more compatible with blood than most plastics, still showthrombogenic characteristics. The first real advance in the preparationof nonthrombogenic materials was described by Dr. Vincent Gott. Themethod used by Dr. Gott comprised treating a graphited surface firstwith Zephiran (benzalkonium chloride) and then with heparin. Materialstreated in this way were nonthrombogenic in vivo for long periods oftime. The major disadvantage, however, with these materials, was thatthe method could only be practiced on rigid plastics and a need stillexists for a suitable flexible nonthrombogenic plastic, as well as amethod of producing the same.

"Various methods have been devised for producing such a material, mostof which involve chemically bonding a quaternary ammonium salt to thepolymer and then heparinizing the same. Usually, this is done byincorporating an amine in the polymer, quaternizing the amine, and thenheparinizing the quaternized material. The disadvantages associated withthese methods are numerous. The materials prepared by these methods haveusually been satisfactory on a small laboratory scale, but could noteasily be scaled up to a practical method. Furthermore, these methodswere quite satisfactory for preparation and evaluation of individualpolymers, the techniques varying from polymer to polymer. A majordrawback, based on these differences in techniques, is thatheparinization of a composite structure containing more than one type ofpolymer could not be easily done. Moreover, many of the techniquesinvolve several steps requiring a variety of reagents, solvents, andreaction conditions."

Many of the disadvantages and drawbacks of the earlier methods forrendering polymeric materials less thrombogenic were removed in themethods described in the above-identified U.S. patent applications.These latter methods comprise:

first absorbing on the surface of the material, a quaternary ammoniumsalt. The material is then "heparinized" by exposure to a salt ofheparin in solution. The heparin is bound to the polymer materialthrough ionic bonds with the surface absorbed quaternary ammonium salt.The treated polymeric materials exhibit an advantageous reduction inthrombogenicity as reflected by extended periods of time during whichthe materials may be in contact with blood without inducing thrombosis.In addition, it has been observed that the quaternary ammoniumsalt-heparin complex treated materials of the prior art have a degree oftoxicity toward the blood or the host animal in which the treatedpolymer is implanted. It is believed that the toxicity is generated byleaching of the quaternary compound from the polymer substrate over aperiod of time.

By the method of our invention, relatively stable articles for use inassociation with whole blood are obtained, which exhibit unexpectedlylow toxicity and unexpectedly reduced thrombogenecity as reflected byunusually long periods of time during which they may be in contact withblood without inducing a thrombosis. By the method of the invention,preformed articles, i.e.; valves, pins, containers, tubing and the like,may be treated to reduce thrombogenicity without increasing toxicity andwithout altering the geometry, configuration and/or dimensions of thearticle. This also obviates the need for post-forming the article asoften necessitated in prior art treatments by shrinking or swelling ordeterioration of the treated article.

SUMMARY OF THE INVENTION

The invention comprises an article for use in association with wholeblood, which comprises;

a solid, polymeric resin substrate; and

a compound of the formula: ##STR2## wherein R is alkyl of 12 to 18carbon atoms, inclusive, R₁ is lower alkyl and A represents the negativeion of a salt of heparin, affixed to the substrate. The moiety A is infact the active heparin moiety, i.e.; the negative ion of heparin havingattached sulfate and sulfonate groups. The moiety A is supplied by saltsof heparin such as sodium heparin, lithium heparin, potassium heparin,calcium heparin and the like.

The term "lower alkyl" as used herein means alkyl of 1 to 6 carbon atomsinclusive such as methyl, ethyl propyl, butyl heptyl, hexyl and isomericforms thereof.

The invention also comprises a method for making the articles of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an embodiment article(medical-surgical tube) of the invention.

FIG. 2 is a view-in-perspective, cross-sectioned in part to show acannula which is advantageously employed in test evaluating the methodof the invention.

FIG. 3 is an isometric view of the cannula of FIG. 2, showing theinsertion of a needle therein for gaining entry into a mamalian vein.

FIG. 4 is a view-in-perspective of a catheter formed of material to betested for blood compatibility, inserted in a mammalian vein with theassistance of the cannula of FIG. 2, which is showncross-sectioned-in-part.

DETAILED DESCRIPTION OF THE INVENTION

The solid, polymeric resin materials advantageously treated by themethod of the invention and used to fabricate articles of the inventionmay be any polymeric resin, natural or synthetic, conventionallyemployed to fabricate articles commonly employed in contact with blood.For example, catheters, artificial blood vessels, valves and likeprosthetics are frequently fabricated from polyethylene, polyacrylics,polypropylene, polyvinyl chloride, polyamides, polyurethanes,polyvinylpyrrolidone, polyvinyl alcohols, cellulose acetate,polystyrene, polytetrafluoroethylene, polyesters such as polyethyleneterephthalate, silicone rubber, natural rubber, polycarbonates and likepolymeric resins and hydrogels, thereof. Such polymeric resins may betreated by the method of the invention and may be employed as thepolymeric resin substrate for the articles of the present invention. Theresin substrate may be rigid or flexible in character, cellular ornon-cellular, porous or non-porous. Also within the scope of theinvention are metal or ceramic materials coated with polymer resins suchas described above.

The polymeric resin substrate may be first formed into any desiredshape, size or configuration. Representative of such are valves, pins,containers, sleeves, connectors, medical-surgical tubing, prostheticdevices and the like of any size.

In accordance with the method of the invention, to the polymeric resinsubstrate there is first affixed by absorption on the surface thereof, aquaternary ammonium salt of the general formula: ##STR3## wherein R andR₁ are as defined previously and X represents a negative monovalent ionsuch as halogen. The term halogen as used herein is embracive ofchlorine, bromine, iodine and fluorine.

The Compounds of Formula (II) are affixed to the polymeric resinsubstrates by their permeating throughout the molecular structure of theresin substrate, i.e.; a chemisorption. It is believed that the C₁₂ toC₁₈ alkyl chain portion of the compounds of formula (II) may also bindto the polymeric resin substrate. The compounds (II) may be chemisorbedinto the polymeric resin substrate by steeping the substrate in adispersion of the compounds (II) (Steeping may be carried out at ambientor at elevated temperatures up to or slightly above the softening pointtemperature for the resin substrate). By the term "softening pointtemperature" we mean the temperature at which the surface of the resinsubstrate becomes pliable due to the additional mobility of thesubstrate molecules. Following fixation of the quaternary ammonium saltcompound (II) to the surface of the polymeric resin substrate, thesurface with affixed compound (II) is "heparinized" by contact with asolution of a salt of the heparin.

The articles of the invention may be prepared by the method of theinvention which as described above first comprises providing a polymericresin substrate, as previously defined, in the desired articleconfiguration and size. As an example, FIG. 1 of the accompanyingdrawing shows a cross-section of a medical-surgical tube 10 of theinvention. The tube 10 comprises a tube polymer substrate 12 and a lumen14. The substrate 12 may be steeped for from about 1 to 72 hours in anaqueous dispersion of a compound of the formula(II) given above at atemperature of from room temperature to at or just above the softeningpoint temperature for the substrate resin. The concentration of compound(II) in the aqueous dispersion is not critical, but advantageously iswithin the range of from about 0.01% to 20% by weight. This assures thata monolayer 16 of relatively high concentration of the compound offormula (II) is provided in contact with the surface of the resinsubstrate. Preferably the aqueous dispersion is degassed before placingthe substrate therein, by heating to a temperature of about 100° C. for15 minutes. This degassing assures obviation of oxidation of thesubstrate surface during steeping. Following the period of steeping, thesubstrate 12 is removed from the dispersion of the compound of formula(II) and allowed to cool to ambient temperatures. The resulting article,upon drying, bears a surface layer 16 as shown in FIG. 1, of thecompound of formula (II) on inner and outer surfaces of substrate 12.The layer 16 actually penetrates to some extent the surface of substrate12, and is chemisorbed or fixed to the substrate 12, as shown in theFIG. 1. The treated substrate may then be washed with water or anorganic solvent for the compound (II) to remove excess compound (II) notfirmly fixed to the substrate 12.

Subsequent to steeping in the dispersion of compound (II) and washing,the treated substrate 12 with its compound (II) layer 16 is then"heparinized" by immersion in an aqueous solution of a salt of heparinsuch as sodium heparin. The temperature at which immersion occurs isadvantageously within the range of from about room temperature to about80° C., but preferably less than the softening point temperature for theresin substrate. The length of immersion is dependent on the temperatureused, but is generally long enough to permit the substrate 12 to pick upat least about 0.1 International Unit heparin per square centimeter ofsubstrate surface. At a temperature of circa 70° C., for example, thisis usually accomplished in about 1 hour, using a heparin solution with aconcentration of from about 1% to saturation, i.e.; circa 20% by weightof sodium heparin, preferably from 5% to saturation. During"heparinization" the negative ion of the sodium heparin complexes withthe positive ion of the compound of formula (II) according to thescheme: ##STR4## wherein R, R₁, X and A are as previously defined. Theproduct, which advantageously has at least 2.0 μg of heparin moiety percm² of surface area attached following "heparinization" is schematicallyshown in FIG. 1 where the layer 18 covering inner and outer layers 16represents the active heparin moiety which is complexed with thecompound (II) of coating layers 16 and in fact also permeates to someextent the substrate 12. It will be appreciated that although A has beenillustrated by the negative ion of sodium heparin in the above schematicformula, it may be provided by any salt compound of heparin.Illustrative of such compounds are lithium heparin, potassium heparin,calcium heparin and the like.

Following the heparinization step, the desired product as schematicallyexemplified in FIG. 1 may be removed from the heparin solution, allowedto cool, washed with water and/or saline, dried and used in contact withblood. The article so obtained will exhibit reduced thrombogenicity.

The following examples illustrate the method of making and using theinvention and represent the best mode contemplated by the inventors ofcarrying out the invention but are not to be construed as limiting theinvention in any way.

The blood compatibility (clotting times) reported were determined by thetest method of our U.S. patent application Ser. No. 899,342 filed Apr.24, 1978, and which was a continuation of our U.S. patent applicationSer. No. 752,247, filed Dec. 20, 1976 and now abandoned. The method maybe carried out as described below in conjunction with the FIGS. 2-4 ofthe accompanying drawings. In the procedure of the test method, it isadvantageous to provide a cannula as shown in FIG. 2, aview-in-perspective of a preferred cannula 20 having a hub 22 tofacilitate holding the cannula 20, a barrel 24 including a tip 26 and atubular extension 28. The extension 28 preferably extends distally fromhub 22 about 1 cm. Barrel 24 and extension 28 are integral and passthrough hub 22 as a unitary, uninterrupted tubular structure as shown inFIG. 2 and are preferably fabricated from a relatively flexible, inertmaterial such as polytetrafluoroethylene. The inner diameter, i.e.; thediameter of the bore traversing cannula 20 is preferably sufficient toreceive in a close fit the tubular form of the material to be tested.

To facilitate entry of the cannula 20 into the blood vessel of a mammal,a tubular stylet needle 30 having a hub 32 is inserted into the bore ofcannula 20 as shown in the isometric view of FIG. 3. As shown, the shankof needle 30 extends out of cannula tip 26. The needle point 34 is asharp surgical edge capable of cutting an entry into a blood vessel. Theneedle 30 may, if desired, include a tight-fitting stylet member (notshown in FIG. 3) removably mounted in its bore to close that bore. Theassembly of cannula 20 and needle 30 may be used to gain entry into theblood vessel, such as vein, of a mammal using conventional blood vesselentry techniques. Following such entry, needle 30 is withdrawn fromcannula 20, leaving the latter's tip 26 positioned in the blood vessel.The tube or catheter 10 of material to be tested for its bloodcompatibility is then inserted through the cannula 20 and into the bloodvessel as shown in FIG. 4. Preferably the catheter extends at least 0.5cm. past the tip 26 so that blood entering the catheter is generally notin contact with cannula 20 before contact with the catheter 10. In eachtest, canines (beagles, 10 to 12 kilograms in weight) are used to supplythe blood required in the test method. The dogs are prepared on the dayof use by first anesthetizing them with combuthal or nembutal byinserting the needle of an infusion set into one of the leg veins. Whenthe vein is punctured, the drug is infused into the vein by a syringeattached to the tubing. The infusion set is left in place during thetest to allow infusion of additional anesthetic as required.

The dog's skin above the jugular vein is then punctured with a standard14 gauge needle which is then withdrawn. A 15 guage cannula 20 as shownin FIG. 2 with an internal stylet needle 30 as shown in FIG. 3 is theninserted through the same puncture to prevent damage to the cannula tip26. The cannula needle 30 is then used to puncture the jugular vein(blood will flow from the needle hub when puncture has occurred).Holding the needle 30 in place, the cannula 20 is slid into the vein andthe needle 30 removed. The cannula 20 is then taped to secure it to thedog. It is now ready for insertion of the test sample, which is providedin the form of tubing or a coating on the inner surface of tubing. Thetubing has a 1.5 mm. outer diameter and an 0.5 mm. inner diameter.

Each test material tube 10 is pre-marked so that when inserted throughthe cannula 20 it will protrude about 0.5 cm. passed the tip 26 into thevein. Each tube for testing is inserted into the cannula 20 whileinfusing 0.9% saline through the tube with a syringe. This prevents thetip of the tube from picking up clots which may form in the cannula 20.After inserting the tube for testing the distal end is lead into a smallflask containing corn oil (to inhibit air interface clotting) and thetimer started when the first drop of blood appears at the distal end ofthe tube for testing. When a drop of blood does not fall in one minutefrom the open end of tube, the timing watch is stopped and the time isrecorded as the blood compatibility time. The tube is then removed.Before inserting subsequent tubes for testing of different or the samematerial, the cannula 20 is washed as follows. The hub 24 of cannula 20is gripped with the left hand and with a needle 30 attached to a syringeof saline, the needle 30 is inserted through the cannula and bloodwithdrawn. This is repeated twice to clean the cannula 20. The next tubefor testing is then inserted, alternating controls with tubes orcatheters of the material to be tested.

When the last tube has been tested, the cannula 20 is removed andpressure applied to the venipuncture until bleeding stops. The dog isrested one week before using again.

The quantitative test to determine the quantity of heparin bound to thesurface of a polymeric resin substrate is carried out as follows.

The method is based on the quantitative removal of the dye Azure A bythe reactive sites of bound heparin. In the assay, heparinized tubingswith known surface area (between 2 and 35 cm²) are exposed to five ml ofa 0.001% aqueous solution of Azure A for 45 minutes at 25° C. Thequantity of dye removed from the solution is determined byspectrophotometric readings made at 630 nm, with a light path of 1 cm.The dye removed is converted to equivalent amounts of heparin by meansof a standard curve prepared by reacting graded amounts of heparin(1-100 micrograms) with five ml of 0.001% Azure A in water, removing theinsoluble heparin dye complex by extraction with four ml of cyclohexane,and quantifying the amounts of dye removed spectrophotometrically. Thestandard curve is then prepared by plotting amount of heparin addedversus absorbance at 630 nm. The amount of heparin present on the tubingcan then be determined by dividing the amount of heparin removed(derived from the standard curve) by the total surface area of thesample.

The toxicity test results reported were by the method described in theU.S. Pharmacopeia, Vol. XVIII at page 927. In general the methodcomprises extracting 10 gm or 120 cm² surface samples of tubing with 20ml. of cotton seed oil at 70° C. for 24 hours. The extract eluate isinjected intraperitoneally in groups of 10 Charles River Mice at a doseof 50 ml eluate per Kg. body weight.

EXAMPLE 1

A tube fabricated from 70% by weight polyethylene and 30% by weightbismuth oxychloride is treated by first steeping in an aqueousdispersion of 15% by weight of dodecylmethylammonium chloride for 16hours at a temperature of 65° C. The steeped tube is then allowed tocool to room temperature, removed from the steeping dispersion andwashed with water at a temperature of 25° C. The washed tube is allowedto dry and is then immersed in an aqueous solution of 9% by weightsodium heparinate for 16 hours at 65° C. The heparinized tube is washedin water at a temperature of 25° C. and then cross-linked by immersionin gluteraldehyde for 4 hours at 65° C. The cross-linked tube is thenwashed with a solution of Triton-100, 5% by weight in water at 25° C.and dried in a vacuum oven at 50° C. for one hour. The dried tube isthen washed twice with 70 ml. portions of distilled water and driedagain. A representative 10 gm. portion of the tube is then subjected totoxicity testing and a representative length is subjected to bloodcompatibility testing. The results are shown in Table I, below.

EXAMPLE 2

This example is not an example of the invention but is made forcomparative purposes.

The procedure for Example 1, supra is repeated in 3 separate runs,except that the 15% dodecylmethylammonium chloride dispersion as used inExample 1 is replaced with 20%, 12% and 2% dispersions, respectively, oftridodecylmethylammonium chloride. The toxicity and blood compatibilitytest results are set forth in Table I, below.

EXAMPLE 3

This example is not an example of the invention but is made forcomparative purposes.

Repeating the procedure of Example 1, supra, but replacing the 15%dispersion of dodecylmethylammonium chloride as used therein with a 15%dispersion of didodecylmethylammonium chloride, the toxicity and bloodcompatibility tests reported in Table I, below, are obtained.

                  TABLE I                                                         ______________________________________                                                                              Blood                                                                Toxicity Compat-                                 Example                      (No. of  ibility                                 No.    Quart. Complex                                                                              Conc.   Mice Dead)                                                                             Minutes                                 ______________________________________                                        1      dodecylmethyl-                                                                              15%     0        186.3                                          ammonium chloride                                                      2      tridodecylmethyl-                                                                           20%     5        142.0                                          ammonium chloride                                                             tridodecylmethyl-                                                                           12%     2        48.0                                           ammonium chloride                                                             tridodecylmethyl-                                                                            2%     0        13.5                                           ammonium chloride                                                      3      didodecylmethyl-                                                                            15%     1        106.0                                          ammonium chloride                                                      ______________________________________                                    

It will be observed from Table I, above, that, at a desirably effectiveblood compatibility level, only the tubing of Example 1 provides anacceptable non-toxicity.

EXAMPLE 4

The procedure of Example 1, supra, is repeated except that thepolyethylene tubing as used therein is replaced with a polyurethane0.020" ID 12 inch length tube. The toxicity and blood compatibilitytests are shown in Table II, below.

EXAMPLE 5

This is not an example of the invention, but is provided for comparativepurposes.

A representative portion of the polyurethane tubing treated in Example4, supra, is tested for toxicity and blood compatibility prior to anytreatment. The results are shown in Table II, below.

                  TABLE II                                                        ______________________________________                                                      Toxicity   Blood Compat-                                                      (No. of    ibility                                              Example       Mice Killed)                                                                             (Minutes)                                            ______________________________________                                        4             0          250.0                                                5 (control)   0          19.7                                                 ______________________________________                                    

EXAMPLE 6

A stainless steel guidewire coated with a 1% solution of polyurethane intetrahydrofuran and dried is treated with dodecylmethylammonium chlorideand heparin following the general procedure set forth in Example 1,supra. The guidewire is then tested for blood compatibility. The testresults are set forth in Table III, below.

EXAMPLE 7

As a control, a stainless steel guide wire coated with polyurethane asin Example 6, supra., is tested before treatment withdodecylmethylammonium chloride and heparin, for blood compatibility. Theresult is shown in Table III, below.

                  TABLE III                                                       ______________________________________                                                                            Clotting                                  Example                             Time                                      No.    Quart. Complex       Conc.   (Minutes)                                 ______________________________________                                        6      dodecylmethylammonium chloride                                                                     15%     170.8                                     7      (control)            --      15.8                                      ______________________________________                                    

EXAMPLE 8

Repeating the procedure of Example 1, supra., four times but in eachcase using a tube fabricated from a material different than thepolyethylene/bismuth composition used therein, there is obtained anarticle of reduced thrombogenicity and toxicity.

The toxicity and blood compatibility test results are shown in Table IV,below, with the identity of the polymer material.

                  TABLE IV                                                        ______________________________________                                                             Blood Compatibility                                                  Toxicity Minutes                                                                (No. of    Before    After                                      Tubing Material                                                                             Mice Dead) Treatment Treatment                                  ______________________________________                                        Silicone rubber                                                                             0          17         62+                                       Polyvinyl chloride                                                                          0          14.7      170+                                       Polyurethane  0          19.7      210+                                       Polytetrafuloroethylene                                                                     0          10.0       70+                                       Nylon -6      0          --        --                                         Polycarbonate 0          --        --                                         Polyoxymethylene                                                                            0          --        --                                         Polypropylene 0          --        --                                         Polystyrene   0          --        --                                         ______________________________________                                    

EXAMPLE 9

The procedure of Example 1, supra., is repeated four times on thepolyurethane tubing, except that in three repetitions, the 9% by weightaqueous dispersion of heparinate as used therein is replaced with 2%, 5%and 20% by weight dispersions of the chloride. The product tubings aresubjected to physical testing. The blood compatibility test results andthe quantity of heparin attached to the article surface is shown inTable V, below, with the concentration of heparin used in thepreparation.

                  TABLE V                                                         ______________________________________                                                    Weight of    Blood                                                Percent     Heparin Attached                                                                           Compatibility                                        Heparin     (μg/cm.sup.2)                                                                           (Minutes)                                            ______________________________________                                        2           0.49         112                                                  5           2.34         172                                                  9           10.85        221                                                  20          18.08        521                                                  ______________________________________                                    

It will be seen from the Example 9 that when the concentration ofheparin is from 5 to 20 percent, the weight of heparin attached issubstantially increased as are the compatibility times.

EXAMPLE 10

The procedure of Example 4, supra., is repeated five times, except thatin each case the dodecylmethylammonium chloride as used therein isreplaced with one of the following:

(A) a 15% aqueous dispersion of decylmethylammonium chloride

(B) a 15% aqueous dispersion of tetradecylmethylammonium chloride

(C) a 10% aqueous dispersion of hexadecylmethylammonium chloride

(D) an 8% aqueous dispersion of octadecylmethylammonium chloride

(E) an 8% ethanol dispersion of dodecylhexylammonium chloride

Representative portions of the tubing obtained are tested for theirtoxicity and blood compatibility. The test results are set forth inTable VI below.

                  TABLE VI                                                        ______________________________________                                                         Toxicity   Blood                                                              (No. of    Compatibility                                     Quart. Complex   Mice Dead) (Minutes)                                         ______________________________________                                        decylmethylammonium                                                                            0          14.1                                              chloride (control)                                                            tetradecylmethylammonium                                                                       0          175.0                                             chloride                                                                      hexadecylmethylammonium                                                                        0          186.0                                             chloride                                                                      octadecylmethylammonium                                                                        0          153.0                                             chloride                                                                      dodecylhexylammonium                                                                           0          180.0                                             chloride                                                                      ______________________________________                                    

The untreated tubing, when tested for blood compatibility as a controlshowed 14.9 minutes.

It will be observed from the Example 10 that with the exception of thecontrol run, the treated resin materials showed both an acceptable bloodcompatibility and freedom from toxicity.

What is claimed is:
 1. A blood compatibility determination method whichcomprisesproviding a test material in the form of a hollow tube havingfirst and second open ends and a length exceeding the length of acannula hereinafter described; providing said cannula of a size anddimension to receive in its bore in a close fitting relationship saidtube, said cannula having first and second ends and a bore communicatingbetween said first and second cannula ends; inserting the first end ofsaid cannula into the blood vessel of a living mammal; inserting thefirst end of said tube into the second end of said cannula, through saidbore and beyond said first end of said cannula, whereby the first end ofsaid tube is positioned in said blood vessel while leaving the secondopen end of the tube outside of the mammal's body, whereby blood flowsfrom said blood vessel, through said first end of said tube, throughsaid tube and out of the open second end of said tube without contactingany solid surface other than the surface of said tube; and measuring thetime period between the initial flow of blood out of the second end ofsaid tube to cessation of said flow.